ArticleNucleic acids research2016
Reversal of DNA damage induced Topoisomerase 2 DNA-protein crosslinks by Tdp2.
Article in Nucleic acids research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
26 citing papers in PubMed.
- EEPD1 evolved a unique DNA clamping dimer protecting reversed replication forks.Nucleic acids research · 2026Article
- Targeting Artemis Sensitizes B Cells to Topoisomerase 2 Poisons by Disrupting DNA-PKcs-Dependent Repair.Research square · 2025Article
- TRIM52 maintains cellular fitness and is under tight proteolytic control by multiple giant E3 ligases.Nature communications · 2025Article
- Article
- MRE11 orchestrates porcine oocyte meiotic progression by modulating the spindle assembly checkpoint.Frontiers in cell and developmental biology · 2025Article
- From the TOP: Formation, recognition and resolution of topoisomerase DNA protein crosslinks.DNA repair · 2024Review
- Dataset from a human-in-the-loop approach to identify functionally important protein residues from literature.Scientific data · 2024Article
- Article
- Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia.Human genetics · 2023Article
- Cell-free circulating tumor RNAs in plasma as the potential prognostic biomarkers in colorectal cancer.Frontiers in oncology · 2023Article
- Molecular basis for processing of topoisomerase 1-triggered DNA damage by Apn2/APE2.Cell reports · 2022Article
- Characterization of N- and C-terminal endogenously tagged Tyrosyl-DNA phosphodiesterase 2 (TDPT-1)microPublication biology · 2022Article
- Topoisomerase-Mediated DNA Damage in Neurological Disorders.Frontiers in aging neuroscience · 2021Review
- Small Molecule Inhibitors Confirm Ubiquitin-Dependent Removal of TOP2-DNA Covalent Complexes.Molecular pharmacology · 2020Article
- Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2.Nucleic acids research · 2020Article
- Excision repair of topoisomerase DNA-protein crosslinks (TOP-DPC).DNA repair · 2020Review
- Inhibition of topoisomerase IIA (Top2α) induces telomeric DNA damage and T cell dysfunction during chronic viral infection.Cell death & disease · 2020Article
- CNCC: an analysis tool to determine genome-wide DNA break end structure at single-nucleotide resolution.BMC genomics · 2020Article
- Molecular mechanisms of topoisomerase 2 DNA-protein crosslink resolution.Cellular and molecular life sciences : CMLS · 2020Review
- Review
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
Mammalian Tyrosyl-DNA phosphodiesterase 2 (Tdp2) reverses Topoisomerase 2 (Top2) DNA-protein crosslinks triggered by Top2 engagement of DNA damage or poisoning by anticancer drugs. Tdp2 deficiencies are linked to neurological disease and cellular sensitivity to Top2 poisons. Herein, we report X-ray crystal structures of ligand-free Tdp2 and Tdp2-DNA complexes with alkylated and abasic DNA that unveil a dynamic Tdp2 active site lid and deep substrate binding trench well-suited for engaging the diverse DNA damage triggers of abortive Top2 reactions. Modeling of a proposed Tdp2 reaction coordinate, combined with mutagenesis and biochemical studies support a single Mg(2+)-ion mechanism assisted by a phosphotyrosyl-arginine cation-π interface. We further identify a Tdp2 active site SNP that ablates Tdp2 Mg(2+) binding and catalytic activity, impairs Tdp2 mediated NHEJ of tyrosine blocked termini, and renders cells sensitive to the anticancer agent etoposide. Collectively, our results provide a structural mechanism for Tdp2 engagement of heterogeneous DNA damage that causes Top2 poisoning, and indicate that evaluation of Tdp2 status may be an important personalized medicine biomarker informing on individual sensitivities to chemotherapeutic Top2 poisons.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.